The two defining criteria of stem cells are multi-potency and self-renewal. Hematopoietic Stem Cells (HSCs) are the only cells within the hematopoietic system that possess the potential for both multi-potency and self-renewal. In the case of HSC, multi-potency is the ability to differentiate into all functional blood cells, while self-renewal is the ability to give rise to identical daughter HSCs without differentiation.
The initial prospective purification of hematopoietic stem cells from mouse BM was achieved utilizing multi-color fluorescence-activated cell sorting and monoclonal antibodies. The resultant population of enriched mouse HSCs had a surface marker phenotype of Thy-1low Lin (Lineage-markers)−Sca-1+, and represented approximately 0.05% of the mouse adult BM cells. Since these initial studies, mouse HSCs have been more extensively purified by identifying and then utilizing additional cell-surface markers to distinguish them from other cells in BM; these included, but were not exclusively single cells that could self-renew and give long-term multilineage maturation. The initial population has been shown to include at least 3 multipotent populations: Long-Term (LT)-HSC, Short-Term (ST)-HSC, and Multi-Potent Progenitor (MPP, a cell population that has lost the self-renewal capacity of HSC). Despite the fact that hematopoietic tissues contain both stem and progenitor cells, rapid and sustained engraftment of syngenic and even of H2 incompatible allogenic hosts can only be achieved with HSC.
The mammalian blood system contains more than ten distinct mature cell types including red blood cells (erythrocyte), megakaryocytes/platelets, myeloid cells (monocyte/macrophage and granulocytes), mast cells, T- and B-lymphocytes, natural killer (NK) cells and dendritic cells (DCs). Such diverse cell types are all derived from a common progenitor cell, i.e. from HSCs. Analyses have shown a hierarchical structure in hematopoietic development in which multi-potency is progressively restricted. HSCs initially give rise to the MPPs which no longer possess self-renewal ability yet keeping full-lineage differentiation potential. Further downstream, MPPs advance to oligopotent progenitors, the common lymphoid progenitor (CLP) and the common myeloid progenitor (CMP). Collectively these oligopotent progenitors then give rise to all the lineage-committed effector cells of the hematopoietic system.
Human HSCs were isolated using similar technologies to those used for mouse HSCs, i.e. isolation of cells representing different stages of differentiation on the basis of cell-surface marker phenotype, coupled with functional assays. For human hematopoiesis, the property of long-term reconstitution of the various cell subsets can be evaluated in xenotransplantations models, utilizing immuno-deficient mice, sometimes transplanted with fetal human hematolymphoid organs for irradiation-resonstitution assays.
In contrast to the high turnover of lineage-restricted progenitors, most of HSCs reside in the ‘quiescent’ G0 phase of the cell cycle. TGF-β/Smad signaling is one of the responsible pathways that maintain quiescence of HSCs, although due to the high redundancy of the Smad molecules (which are the intracellular transducer of TGF signaling), and early embryonic lethality of most Smad and TGF-β knockout mouse models, in vivo elucidation of the role of the TGF/Smad signaling pathway in HSC function has proven difficult. Another proposed cue for HSC quiescence is Ang-1/Tie2. Tie2 is a receptor tyrosine kinase expressed on endothelial cells and HSCs.
The blood system reflects the balance of two essential abilities of HSC, self-renewal and differentiation. Intensive studies have revealed the hierarchical structure of the blood system and key molecules regulating LT-HSC. However, the entire picture of the molecular interactions orchestrating LT-HSC fate is yet unclear. Synergies between highly developed biological and molecular approaches and rapidly emerging systems approaches are needed to integrate and accelerate understanding of this cell population.